BACKGROUND: Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD. METHODS: We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL. RESULTS: Forty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors (P < 0.001), a later onset age (P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250-300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain. CONCLUSIONS HTRA1-related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1-related autosomal dominant CSVD.
Cerebral Infarction ; Cerebral Small Vessel Diseases/genetics* ; Heterozygote ; High-Temperature Requirement A Serine Peptidase 1/genetics* ; Humans ; Leukoencephalopathies/genetics* ; Mutation/genetics*

OBJECTIVETo evaluate the correlation between the beta-fibrinogen gene-455G/A polymorphism and cerebral infarction in Chinese population by means of meta-analysis.

METHODSGenetic association studies on evaluating the beta-fibrinogen gene -455G/A polymorphism and cerebral infarction involving Chinese population published before December 2005 were collected from database of PubMed, EMBASE, and CNKI. All the data in literature were abstracted based on the defined selection criteria by two independent investigators. Publication bias was tested by funnel plot and the odd ratios of all studies were combined dependent on the result of heterogeneity test among the individual studies. The software Review Manager (Version 4.2) was used for meta-analysis.

RESULTSEleven studies including 1405 patients and 1600 controls met the selection criteria. There was no publication bias in 11 reviewed studies. Heterogeneity test of reviewed studies showed statistically significant differences (chi2=24.58, P=0.006) among the ORs of individual studies. The combined OR of 11 studies of susceptibility to cerebral infarction in -455A allele carriers compared with the -455G/G wild homozygotes was 1.33 (95%CI 1.04-1.71, P=0.02). In the patients with cerebral infarction in 6 studies, the summarized average plasma fibrinogen level of allele A carrier was 0.29 g/L (95%CI 0.14-0.44, P=0.0002) higher than that of -455G/G homozygous ones.

CONCLUSIONSbeta-fibrinogen gene -455G/A polymorphism might contribute to susceptibility of cerebral infarction in Chinese population; allele A increases the individual susceptibility to the disease.

Asian Continental Ancestry Group ; genetics ; Cerebral Infarction ; blood ; Fibrinogen ; analysis ; genetics ; Humans ; Polymorphism, Genetic

OBJECTIVEThe results of studies on association between -148C/T polymorphism in promoter region of beta-fibrinogen gene and susceptibility to cerebral infarction in Chinese population are controversial. In this study, we summarize the results of published works in this field by a meta-analysis. Data sources Genetic association studies evaluating the beta-fibrinogen gene -148C/T polymorphisms and cerebral infarction involving Chinese population published before December 2005 were collected from PubMed, EMBASE and CNKI. Study selection Case control studies involving unrelated, Han subjects aged from 18 to 80 years, and the internationally recognized diagnostic standard of cerebral infarction and genotype frequencies in control group consistent with Hardy-Weinberg equilibrium were used. Publication bias was tested by funnel plot and the odds ratios of all studies were combined dependent on the result of heterogeneity test among the individual studies. The software Review Manager (Version 4.2) was used for meta-analysis.

RESULTSEleven studies including 1223 patients and 1433 controls met the selection criteria. There was no heterogeneity among the odds ratios (ORs) of individual studies (chi(2) = 17.82, P = 0.06). The combined OR of susceptibility to cerebral infarction in -148T allele carriers compared to the wild homozygote was 1.32 (95% CI 1.12 to 1.55, P = 0.0008). In the patients with cerebral infarction, the average plasma fibrinogen level of allele T carrier was 0.42 g/L (95% CI 0.29 to 0.54, P < 0.001), higher than that of -148C/C homozygous ones.

CONCLUSIONSbeta-fibrinogen gene -148C/T polymorphism might contribute to susceptibility to cerebral infarction in Han Chinese. To reach a definitive conclusion, further gene to gene and gene to environment interactions studies on beta-fibrinogen polymorphisms and cerebral infarction with large sample size are required.

Cerebral Infarction ; genetics ; China ; ethnology ; Fibrinogen ; analysis ; genetics ; Genetic Predisposition to Disease ; Humans ; Polymorphism, Genetic

OBJECTIVETo investigate the association between the plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene polymorphism and the occurrence of myocardial and cerebrovascular infarctions in individuals from Tianjin, China.

METHODSThe PAI-1 genotype was determined using allele-specific polymerase chain reaction (AS-PCR) in 56 myocardial infarction (MI) patients, 54 cerebrovascular infarction (CI) patients and 83 unrelated healthy controls. All subjects' clinical features and plasma PAI-1 activity levels were determined.

RESULTSThe PAI-1 genotype distribution frequency of the single guanine deletion/insertion 4G/5G polymorphism (located -675 bp upstream from the start of transcription) significantly differed between the patients and healthy controls. In the MI group, the 4G/4G-genotype frequency was increased, but the 4G/5G-genotype is decreased when compared to the control group. In the CI group, both the 4G/4G- and 4G/5G -genotypes occurred at a lower frequency than those in the control group (P < 0.001). The plasma PAI-1 activity level in the MI group was lowered as the presence of the 4G allele decreases. In the CI group, the frequency of 5G/5G was much higher than that of the control group (P < 0.001). The plasma PAI-1 activity level in the CI group was elevated as the presence of the 5G allele increased. Furthermore, positive correlation between triglyceride, glucose levels and PAI-1 activity were found in all three groups (P < 0.001).

CONCLUSIONSThe PAI-1 4G/5G gene polymorphism is associated with a higher risk of MI and CI in individuals in Tianjin, China. The deletion/insertion polymorphism is probably an important hereditary risk factor for heart diseases. Moreover, triglyceride and glucose levels of plasma have functional importance in regulating PAI-1 activity.

Aged ; Asian Continental Ancestry Group ; genetics ; Cerebral Infarction ; genetics ; China ; epidemiology ; Female ; Gene Deletion ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; genetics ; Plasminogen Activator Inhibitor 1 ; genetics ; Polymorphism, Genetic

Cerebral ischemia is one of the most common diseases in China, and the drug pair of Chuanxiong Rhizoma and Paeoniae Radix Rubra can intervene in cerebral ischemia to reduce the inflammatory response of cerebral ischemia and apoptosis. To reveal the intervention mechanism of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia systematically, computer network pharmacology technology was used in this paper to predict the target and signaling pathway of the drug pair on the intervention of cerebral ischemia, and then the molecular docking technology was used to further analyze the mechanism of the intervention. The target results were then verified by the rat cerebral ischemia model. The target network results showed that the active compounds of Chuanxiong Rhizoma-Paeoniae Radix Rubra for cerebral ischemic disease contained 30 compounds, 38 targets and 9 pathways. The main compounds included phenolic acids in Chuanxiong Rhizoma and monoterpene glycosides in Paeoniae Radix Rubra. The key targets involved mitogen-activated protein kinase 1(MAPK1), steroid receptor coactivator(SRC), epidermal growth factor receptor(EGFR), mitogen-activated protein kinase 14(MAPK14), caspase-3(CASP3), caspase-7(CASP7), estrogen receptor 1(ESR1), and mitogen-activated protein kinase 8(MAPK8), etc. The target gene functions were biased towards protein kinase activity, protein autophosphorylation, peptidyl-serine phosphorylation and protein serine/threonine kinase activity, etc. The important KEGG pathways involved Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. Molecular docking results showed that catechin, oxypaeoniflorin, albiflorin, paeoniflorin and benzoylpaeoniflorin had strong binding ability with MAPK1, SRC, EGFR, MAPK14 and CASP7. MCAO rat experimental results showed that Chuanxiong Rhizoma-Paeoniae Radix Rubra significantly improved the cerebral ischemia injury and interstitial edema, and significantly reduced the activation of caspase-7 and the phosphorylation of ERK1/2. The Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair alleviated cerebral ischemia injury through a network model of multi-phenotype intervention by promoting cell proliferation and differentiation, reducing inflammatory factor expression, protecting nerve cells from death and figh-ting against neuronal cell apoptosis, with its action signaling pathway most related to Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. This study provides the basis for clinical intervention of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia, and also provides ideas for the modernization of drug pairs.
Animals ; Brain Ischemia/genetics* ; Cerebral Infarction ; Drugs, Chinese Herbal ; Molecular Docking Simulation ; Paeonia ; Rats ; Rhizome

OBJECTIVETo assess the association of extracellular superoxide dismutase (EC-SOD) gene methylation with cerebral infarction.

METHODSEighty-three patients with cerebral infarction and 94 healthy controls were enrolled. Based on cerebral MR findings, the size of infarction, extent of intracranial atherosclerosis, the National Institutes of Health Stroke Scale (NIHSS) score, and Barthel index were calculated. Methylation-specific PCR was used to analyze the methylation status of the EC-SOD gene in peripheral blood samples and its correlation with cerebral infarction.

RESULTSThe rate of EC-SOD gene promoter region methylation of the cerebral infarction group was lower than that of the control group (30.1% vs. 53.2%, P < 0.05). Patients with larger area of cerebral infarction (>4 cm in diameter) showed a lower methylation rate than those with a smaller cerebral infarction (0 vs. 39.1%, P < 0.05). Based on their cerebral MRA, 57 patients were divided into none, mild, moderate, and severe cerebral arteriosclerosis groups. The rate of EC-SOD gene methylation of the four groups showed a downward trend (at 45.5%, 42.9%, 23.8%, and 14.3%, respectively), though no statistical significance was found (P > 0.05). For the cerebral infarction group, those with higher rate of methylation had lower NIHSS scores (P < 0.05) but insignificantly higher Barthel index (P > 0.05).

CONCLUSIONThe EC-SOD methylation frequency of case group was lower than the control group. The methylation status is associated with the size of cerebral infarction, degree of cerebral arteriosclerosis and severity of neurological impairment.

Aged ; Cerebral Infarction ; genetics ; DNA Methylation ; Extracellular Space ; enzymology ; Female ; Humans ; Male ; Middle Aged ; Superoxide Dismutase ; genetics

Aged ; Case-Control Studies ; Cerebral Infarction ; blood ; genetics ; Female ; Fibrinogen ; genetics ; metabolism ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic

OBJECTIVE: To assess the influence of apolipoprotein E (ApoE) gene polymorphisms on the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. METHODS: One hundred and six patients with ischemic cerebral infarction who orally took lipid-lowering statins for 3 months were enrolled. Changes in serum triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) before and after the drug administration were analyzed. ApoE gene polymorphisms were detected by real-time fluorescent quantitative PCR, and genotypes of ApoE gene in patients with different effects were compared. RESULTS: The detection rates for E2/E2, E2/E3, E3/E3, E2/E4 and E3/E4 genotypes were 0.94%, 11.32%, 63.21%, 1.89% and 22.64%, respectively. And the detection rates for E2, E3 and E4 alleles were 7.55%, 80.19% and 12.26%, respectively. Biochemical phenotypes included E2 type (13 cases, 12.26%), E3 type (69 cases, 65.09%) and E4 type (24 cases, 22.65%). Before administration, TG and TC of E2 type were the highest (P<0.05), but no significant difference was detected in HDL-C and LDL-C among the three phenotypes (P>0.05).Following the drug administration, TG, TC and LDL-C were decreased, while HDL-C was increased. HDL-C of E2 type was the highest, TC and LDL-C of E4 type were the highest (P<0.05). The E3/E3 ratio in low-efficiency group at admission was lower than that in the high-efficiency group, while the E3/E4 ratio was higher than that in the high-efficiency group (P<0.05). The proportion of E3 allele in low-efficiency group was lower than that in high-efficiency group, while the proportion of E4 allele was higher than that in high-efficiency group (P<0.05). CONCLUSION ApoE gene polymorphisms are closely correlated with the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. The lipid-lowering effects are more significant in patients with E2 and E3 genotypes, but were poor in those with the E4 genotype. Personalized regimens should be applied.
Apolipoproteins E/genetics* ; Cerebral Infarction/genetics* ; Genotype ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Lipids ; Polymorphism, Genetic ; Triglycerides

Moyamoya disease is characterized by bilateral stenosis or occlusion of distal internal carotid artery (ICA) bifurcation including its proximal branches and abnormal vascular network (moyamoya vessel, MMV) in the vicinity of the arterial occlusions. It is the most common pediatric cerebrovascular disease in Eastern Asia, particularly in Korea and Japan. The etiology is still unknown, but much about the pathology from autopsies, factors involved in its pathogenesis, and its genetics have been studied and reported. It may cause ischemic attacks or cerebral infarctions in children and cerebral hemorrhage in adults. Because of its aggressive clinical course in very young children, the need for early detection and treatment has been recognized. Magnetic resonance imaging (MRI)/MR angiography (MRA), cerebral hemodynamic studies, and cerebral angiography are used for the diagnosis. The treatment basically focuses on prevention of further ischemia and infarction through revascularization. Technically, direct and indirect bypass methods are used. The treatment strategy needs to be individualized in each patient. Outcomes of revascularization procedures are excellent in preventing transient ischemic attacks (TIAs) in most patients.
Adult ; Angiography ; Autopsy ; Carotid Artery, Internal ; Cerebral Angiography ; Cerebral Hemorrhage ; Cerebral Infarction ; Child ; Constriction, Pathologic ; Diagnosis ; Far East ; Genetics ; Hemodynamics ; Humans ; Infarction ; Ischemia ; Ischemic Attack, Transient ; Japan ; Korea ; Magnetic Resonance Imaging ; Moyamoya Disease* ; Pathology

Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases such as stroke and Alzheimer's disease. Apo-1/Fas gene is one of the mediators of apoptosis in stroke. MvaI polymorphism is the first polymorphic marker identified in the Apo-1/Fas gene promoter, which was typed by PCR and followed by MvaI digestion and gel electrophoresis. DNA isolated from peripheral blood collected from 91 stroke patients and 103 healthy blood donors was used for genotypes of GG, GA and AA by sequence specific primer PCR. MvaI polymorphism was examined based on Fas gene promotor region by restriction fragment length polymorphism (RFLP). The Fas-GG genotype was the least frequent in patients with stroke and healthy controls (P = 0.57). In normal Korean controls the MvaI polymorphism GA, AA and GG were 48.6%, 34.9% and 16.5%. In stroke patients were 56.2%, 29.6% and 14.2% respectively. And the allelic frequencies of MvaI*2 (G) allele were less frequent than MvaI*1 (A) allele in patients with stroke and healthy controls (P = 0.76). In normal Korean controls MvaI*1 (A) and MvaI*2 (G) alleles were 59.2% and 40.8%. In stroke patients were 57.6% and 42.4%, respectively. Our results, pending confirmation in a larger study, indicate that the Fas genotype may not appear to be a risk factor for stroke in Korean stroke patients.
Adult ; Aged ; Antigens, CD95/*genetics ; Cerebral Infarction/*genetics ; Comparative Study ; Female ; Gene Frequency ; Genotype ; Human ; Korea ; Male ; Middle Aged ; *Polymorphism (Genetics) ; *Promoter Regions (Genetics)